We have created a mouse model for the human disorder ataxia-telangiectasia. These mice recapitulate the human phenotype. We have gone on to use these mice to study the molecular basis of infertility and radiation sensitivity. Atm-deficient mice are completely infertile. To gain further insight into the role of Atm in meiosis, we have carefully examined meiosis in Atm-deficient mice, and in mice doubly deficient for Atm and p53 or Atm and p21. Male and female gametogenesis are severely disrupted in Atm-deficient mice as early as leptotene of prophase I, resulting in apoptotic degeneration. Rad51 foci are not assembled properly on unpaired axial elements in leptotene of mutant spermatocytes, and p53, p21 and Bax are elevated in these mutant testes. In Atm/p53 or Atm/p21 double mutants, spermatogenesis progresses further into pachytene stages, but not to diplotene. Assembly of Rad51 foci on axial elements remains defective, and p53, p21 and Bax remain elevated unless genetically eliminated. Our results demonstrate that Atm is absolutely required for Rad51 assembly onto the axial elements, as well as for suppressing p53, p21 and Bax levels, suggesting that Atm participates in the regulation or surveillance of meiotic recombination and progression. The mislocalization of Rad51 in the Atm -/- mice is of particular interest, since Rad51 is important for double strand break repair and meiotic recombination, and associates with both BRCA1 and BRCA2. In response to ionizing radiation (IR), Atm is part of a DNA damage-response pathway that involves p53. p53 is a multifunctional protein that simultaneously regulates distinct downstream pathways controlling cell cycle progression and apoptosis. However, the mechanisms by which p53 differentially activates downstream pathways are unknown. Our data demonstrate that after IR, Atm acts via p53 to activate cell cycle checkpoint pathways and induce p21, but p53-dependent or p53-independent apoptotic responses and Bax induction are independent of Atm function. IR-induced thymic apoptosis was supressed in in Atm/p53 double mutant mice, but not in Atm/p21 double mutants, demonstrating that these IR-mediated apoptotic responses are p53-dependent. Our results support a model in which upstream effectors such as Atm selectively activate p53 to regulate specific downstream pathways, providing a mechanism for controling distinct cell cycle and apoptotic responses.